Particle size distributions are extremely important in the preparation of pharmaceutical materials. Dissolution profiles of orally-ingested drugs, for instance, strongly depend on available surface area. It is estimated that about 40% of drugs fail in development due to difficulties in pharmacokinetics, most commonly related to their solubility properties. This is perhaps not surprising; in order to be effective, a drug typically has to be able to cross cell membranes, requiring a certain degree of lipophilicity. Solubility in the body, on the other hand, requires hydrophilicity. Controlling the surface area of particles in order to expedite the solvation of partly hydrophobic particles is one way to help combat the solubility problem.
There are many other reasons why controlling particle size is important to the pharmaceutical industry. Aerosol drugs, for example, are often delivered as suspensions of particles (metered-dose inhalers) or as dry powders (dry powder inhalers). Large particles may be unable to “make the turn” and may lodge in the back of the throat rather than continue on to the lungs. Particles hitting the throat in this way are more likely to be responsible for undesirable side effects than to deliver a therapeutic benefit. If the particles are too small they do not settle in the lungs before exhalation and are simply expelled from the body. There is a narrow size distribution, therefore, that is considered acceptable for aerosol drug materials, usually reported as an aerodynamic diameter of about 0.5-5 μm.
Parenteral drugs delivered by intravenous, subcutaneous, or intramuscular injection may be slurries of particles or emulsions rather than solutions. The particle size of the drug may influence the rate of release, and in the case of intravenous injection it is critical that particles are not larger than about 5 μm; otherwise, the patient may suffer a potentially fatal pulmonary embolism. Particle size is also important for other drug delivery methods, such as buccal delivery and rectal delivery.
Despite the importance of controlling the particle size of pharmaceutical agents, industrial-scale approaches to synthesizing drug particles are generally unsatisfactory. It is common to micronize large crystals mechanically by jet milling, wet or dry milling, or similar techniques. However, these methods have a number of shortcomings, including producing broad crystal size distributions with nonuniform morphologies, introducing defects (which may influence shelf life and solubility profile), inducing phase changes among polymorphs, producing amorphous materials, and/or causing electrostatic charging and agglomeration. Drug particles subjected to such mechanical methods are commonly waxy solids that reagglomerate badly after milling.
It would be advantageous to be able to prepare high surface area drug crystals and other particles in a controlled process without the need for post-crystallization modification.